Hereditary Alpha Tryptasemia: Validation of a Single-Well Multiplex Digital Droplet PCR Assay in a Cohort of Symptomatic Patients.

BACKGROUND: Hereditary alpha tryptasemia (HαT) has significant prevalence and potential morbidity in the general population. However, it remains largely undiagnosed in routine clinical diagnostics due to low availability of efficient assessment methods. To address this issue, we developed a reliable and efficient single-well multiplex digital droplet PCR assay. METHODS: The assay was based on the reconstruction of the TPSAB1 gene through quantification of the ratio of α- and ß-tryptase copy number variants (CNV) in a single-well measurement. We performed analytical validation by determining CNV measurement clustering around the expected copy numbers in 281 cases and determined the diagnostic accuracy of basal serum tryptase (BST) to predict HαT and HαT subtypes in 141 symptomatic patients. RESULTS: The assay determined α- and ß-tryptase CNVs with an overall accuracy, expressed as a 99% prediction interval, of 0.03 ± 0.27 copy numbers. The optimal BST cutoff level to predict HαT in symptomatic patients, who had no other explanation for relatively high tryptase levels (i.e., no diagnosis of systemic mastocytosis, myeloid neoplasm, or end-stage renal failure), was 9.2 ng/mL (sensitivity: 98.1%; specificity: 96.6%). HαT showed a linear gene-dose effect, with an average gene-dose increase of 7.5 ng/mL per extra α-tryptase gene. CONCLUSION: Our single-well multiplex digital droplet PCR assay accurately determined HαT and could be implemented as a state-of-the-art routine diagnostic test. The assay demonstrated a strong correlation with BST and the optimal threshold for identifying HαT in symptomatic patients with unexplained high tryptase concentrations was at a BST level of 9.2 ng/mL.

Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study.

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.

The effect of different abutment materials on peri-implant tissues-A systematic review and meta-analysis.

OBJECTIVES: In patients with dental implants, what is the effect of transmucosal components made of materials other than titanium (alloys) compared to titanium (alloys) on the surrounding peri-implant tissues after at least 1 year? MATERIALS AND METHODS: This systematic review included eligible randomized controlled trials identified through an electronic search (Medline, Embase and Web of Science) comparing alternative abutment materials versus titanium (alloy) abutments with a minimum follow-up of 1 year and including at least 10 patients/group. Primary outcomes were peri-implant marginal bone level (MBL) and probing depth (PD), these were evaluated based on meta-analyses. Abutment survival, biological and technical complications and aesthetic outcomes were the secondary outcomes. The risk of bias was assessed with the RoB2-tool. This review is registered in PROSPERO with the number (CRD42022376487). RESULTS: From 5129 titles, 580 abstracts were selected, and 111 full-text articles were screened. Finally, 12 articles could be included. Concerning the primary outcomes (MBL and PD), no differences could be seen between titanium abutment and zirconia or alumina abutments, not after 1 year (MBL: zirconia: MD = -0.24, 95% CI: -0.65 to 0.16, alumina: MD = -0.06, 95% CI: -0.29 to 0.17) (PD: zirconia: MD = -0.06, 95% CI: -0.41 to 0.30, alumina: MD = -0.29, 95% CI: -0.96 to 0.38), nor after 5 years. Additionally, no differences were found concerning the biological complications and aesthetic outcomes. The most important technical finding was abutment fracture in the ceramic group and chipping of the veneering material. CONCLUSIONS: Biologically, titanium and zirconia abutments seem to function equally up to 5 years after placement.

Ganciclovir therapeutic drug monitoring in transplant recipients.

BACKGROUND: The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance. OBJECTIVES: To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population. METHODS: An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1-2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2-4 mg/L and an AUC24h of 80-120 mg·h/L were aimed for. RESULTS: Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2-6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline. CONCLUSIONS: This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.

[Heredity and cancer]. / Hérédité et cancer.

A personal or family history of cancer has now become the primary cause of genetic consultations. In recent years, various genes have been identified that are associated with a more or less marked genetic predisposition to the development of cancers. The syndrome associated with the hereditary risk of breast and ovarian cancer and the Lynch syndrome are the most frequent ones, but there are many other, much less common, situations associated with familial cancer risk. In most cases, there are clear recommendations regarding the indications for genetic testing and the follow-up of patients identified as having a predisposition to cancer. At the CHU of Liège, we currently perform more than 1.400 oncogenetic consultations per year and we maintain a positivity rate of genetic tests performed in this indication higher than 10%. In this way, we allow a multidisciplinary care of patients with a high oncological risk and participate in a prevention and surveillance activity. We also pay increasing attention to the hereditary risk associated with pediatric cancers and to patients with multiple cancers, especially when these develop at an early age. Finally, the oncogenetic consultation must consider the psychological, ethical and legal aspects of a diagnosis that involves the patient and his or her future, but also the whole family.

Une histoire personnelle ou familiale de cancer est aujourd'hui devenue la première cause de consultation en génétique. Au cours de ces dernières années, en effet, différents gènes associés à une prédisposition génétique plus ou moins marquée au développement de pathologies cancéreuses ont été identifiés. Le syndrome de prédisposition héréditaire au cancer du sein et de l'ovaire (HBOC : Hereditary Breast and/or Ovarian Cancer) et le syndrome de Lynch sont les plus fréquents. Mais il existe une multitude d'autres situations beaucoup moins fréquentes associées à un risque familial de cancer. Dans la plupart des cas, des recommandations claires existent quant à l'indication des tests génétiques et quant au suivi proposé au patient chez qui une prédisposition au cancer est identifiée. Au CHU de Liège, nous réalisons actuellement plus de 1.400 consultations d'oncogénétique par an et nous maintenons un taux de positivité des tests génétiques réalisés dans cette indication supérieur à 10 %. De cette façon, nous permettons une prise en charge multidisciplinaire des patients avec un haut risque oncologique et participons à une activité de prévention et de surveillance. Nous portons une attention croissante aux enfants et adolescents présentant un cancer, d'une part, et aux adultes ayant présenté de multiples cancers, d'autre part, particulièrement lorsque ceux-ci se développent à un âge précoce. Enfin, la consultation d'oncogénétique doit tenir compte des aspects psychologiques, éthiques et légaux, liés à un diagnostic qui implique le patient et son avenir, mais également l'ensemble de la famille.

[A multidisciplinary approach for accelerated orthodontics]. / Une approche pluridisciplinaire pour l'accélération des traitements en orthodontie.

An increasing number of adult patients are seeking orthodontic treatment and several surgical and non-surgical methods have been developed to reduce the overall treatment time. Two randomized controlled clinical trials, performed in our University Hospital, demonstrated that the piezocision surgery - minimally invasive corticotomies - decreased the overall orthodontic treatment time by 43 % - effect during 4 to 6 months after the surgery - without any further clinical and radiological adverse effects. In addition, the use of a custom-made orthodontic system - brackets and arches - optimized the acceleration in the fine-tuning phase of orthodontic treatment. Finally, the combination of the two techniques is therefore relevant to maximize the reduction of the orthodontic treatment time. Fundamentally, our preclinical studies in rats have highlighted the biological phenomena underlying piezocision with an important bone demineralization and osteoclast recruitment associated with a predominant expression of the RANKL-OPG duo.

La demande des patients adultes pour entreprendre des traitements orthodontiques est en augmentation constante; cependant, la longueur des traitements reste souvent un frein. Dès lors, plusieurs techniques chirurgicales et non chirurgicales ont été mises au point afin de réduire le temps de traitement orthodontique. Deux études cliniques contrôlées randomisées, réalisées au sein de notre hôpital universitaire, ont démontré que la technique de piézocision - corticotomies minimalement invasives - permet de réduire jusqu'à 43 % le temps de traitement orthodontique - au cours des 4 à 6 mois après l'intervention - et ce, sans effets secondaires tant sur le plan clinique que radiologique. De plus, l'utilisation d'un système orthodontique customisé - employant des attaches et des arcs sur mesure - permet d'optimiser l'accélération du déplacement dentaire dans la phase de finition du traitement orthodontique. Finalement, la combinaison des deux techniques est donc pertinente pour maximaliser la réduction du temps de traitement en orthodontie. Par ailleurs, sur le plan fondamental, nous avons étudié, dans des essais précliniques chez le rat, les phénomènes biologiques sous-jacents à la piézocision à savoir une déminéralisation osseuse et un recrutement d'ostéoclastes plus important associés à une expression prédominante du duo RANKL-OPG.

Role of FDG PET/CT in monitoring treatment response in patients with invasive fungal infections.

INTRODUCTION: Invasive fungal infections (IFIs) occur mostly in immunosuppressed patients and can be life-threatening. Inadequate treatment is associated with high morbidity and mortality. We examined the role of 2-fluorodeoxyglucose positron emission tomography integrated with CT (FDG-PET/CT) in monitoring IFIs and therapy decision-making, and evaluated the role of baseline metabolic parameters in predicting the metabolic response. METHODS: All patients between October 2009 and March 2018, diagnosed with IFIs, treated with antifungal drugs, and who underwent FDG-PET/CT at baseline and at one or more timepoints during treatment were retrospectively included. The electronic patient files were reviewed for pathology, microbiology, and laboratory findings. All FDG-PET/CT scans were performed according to standardized European Association of Nuclear Medicine/EANM Research Limited (EANM/EARL) protocols. For each scan, the global total lesion glycolysis (TLG) and metabolic volume (MV), highest maximum standardized uptake value (SUVmax), and peak standardized uptake value (SUVpeak) were determined. The role of FDG-PET/CT on monitoring antifungal therapy was assessed by looking at the clinical decision made as result of the scan. Furthermore, the added value of the baseline metabolic parameters in predicting metabolic response to the antifungal treatment was evaluated. RESULTS: Twenty-eight patients with in total 98 FDG-PET/CT scans were included with a mean age of 43 ± 22 years. FDG-PET/CT altered management in 14 out of the 28 patients (50%). At the final FDG-PET/CT scan, 19 (68%) had a complete metabolic response (CMR), seven a partial response and two patients were defined as having progressive disease. Using receiver operative analysis, the cut-off value, sensitivity, specificity, and significance for the baseline TLG and MV to discriminate patients with CMR were 160, 94%, 100%, p < 0.001 and 60, 84%, 75%, p = 0.001 respectively. CONCLUSION: FDG-PET/CT is useful in the monitoring of IFIs resulting in management therapy change in half of the patients. Baseline TLG and MV were found to be able to predict the metabolic response to antifungal treatment.

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations.

Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty-seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1-7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8-2.7) for prophylaxis and 1.76 mg/L (IQR 1.3-2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.

The diagnosis and treatment of invasive aspergillosis in Dutch haematology units facing a rapidly increasing prevalence of azole-resistance. A nationwide survey and rationale for the DB-MSG 002 study protocol.

Patients with haematological malignancies are at risk for invasive fungal diseases (IFD). A survey was conducted in all Dutch academic haematology centres on their current diagnostic, prophylactic and therapeutic approach towards IFD in the context of azole-resistance. In all 8 centres, a haematologist and microbiologist filled in the questionnaire that focused on different subgroups of haematology patients. Fungal prophylaxis during neutropaenia was directed against Candida and consisted of fluconazole and/or amphotericin B suspension. Mould-active prophylaxis was given to acute myeloid leukaemia patients during chemotherapy in 2 of 8 centres. All centres used azole prophylaxis in a subset of patients with graft-versus-host disease. A uniform approach towards the diagnosis and treatment of IFD and in particular azole-resistant Aspergillus fumigatus was lacking. In 2017, all centres agreed to implement a uniform diagnostic and treatment algorithm regarding invasive aspergillosis with a central role for comprehensive diagnostics and PCR-based detection of azole-resistance. This study (DB-MSG 002) will re-evaluate this algorithm when 280 patients have been treated. A heterogeneous approach towards antifungal prophylaxis, diagnosis and treatment was apparent in the Netherlands. Facing triazole-resistance, consensus was reached on the implementation of a uniform diagnostic approach in all 8 centres.

Voriconazole metabolism is influenced by severe inflammation: a prospective study.

BACKGROUND: During an infection or inflammation, several drug-metabolizing enzymes in the liver are down-regulated, including cytochrome P450 iso-enzymes. Since voriconazole is extensively metabolized by cytochrome P450 iso-enzymes, the metabolism of voriconazole can be influenced during inflammation via reduced clearance of the drug, resulting in higher voriconazole trough concentrations. OBJECTIVE: To investigate prospectively the influence of inflammation on voriconazole metabolism and voriconazole trough concentrations. METHODS: A prospective observational study was performed at the University Medical Center Groningen. Patients were eligible for inclusion if they were ≥18 years old and treated with voriconazole. Voriconazole and voriconazole-N-oxide concentrations were determined in discarded blood samples. To determine the degree of inflammation, C-reactive protein (CRP) concentrations were used. Subsequently, a longitudinal data analysis was performed to assess the effect of inflammation on the metabolic ratio and voriconazole trough concentration. RESULTS: Thirty-four patients were included. In total 489 voriconazole trough concentrations were included in the longitudinal data analysis. This analysis showed that inflammation, reflected by CRP concentrations, significantly influenced the metabolic ratio, voriconazole trough concentration and voriconazole-N-oxide concentration (all P < 0.001), when corrected for other factors that could influence voriconazole metabolism. The metabolic ratio was decreased by 0.99229N and the voriconazole-N-oxide concentration by 0.99775N, while the voriconazole trough concentration was increased by 1.005321N, where N is the difference in CRP units (in mg/L). CONCLUSIONS: This study shows that voriconazole metabolism is decreased during inflammation, resulting in higher voriconazole trough concentrations. Therefore, frequent monitoring of voriconazole serum concentrations is recommended during and following severe inflammation.

Voriconazole Therapeutic Drug Monitoring Practices in Intensive Care.

BACKGROUND: Routine therapeutic drug monitoring of voriconazole seems to be beneficial. This study investigated the therapeutic drug monitoring practices in intensive care to derive possible recommendations for improvement. METHODS: A retrospective chart review was performed for patients aged ≥18 years who started treatment with voriconazole, which lasted for at least 3 days while being admitted to an intensive care unit to assess possible differences between the patients with and without voriconazole trough concentrations measured. RESULTS: In 64 (76%) of the 84 patients, voriconazole trough concentrations were measured. The groups differed significantly with respect to the duration of voriconazole treatment and intensive care unit admission. Time of sampling was very early and therefore inappropriate for 49% of the first measured voriconazole trough concentrations and in 48% of the subsequent measured concentrations. Of the 349 trough concentrations measured, 129 (37%) were outside the therapeutic window. In 11% of these cases, no recommendation was provided without identifiable reason. In addition, 27% of recommended dose adjustments were not implemented, probably because the advice was not suited for the specific clinical situation. CONCLUSIONS: The performance of voriconazole therapeutic drug monitoring can still be improved although voriconazole concentrations were monitored in most patients. A multidisciplinary approach-for instance by means of antifungal stewardship-will probably be able to overcome problems encountered such as timing of sampling, incompleteness of data in clinical context, and lack of implementation of recommendations.

Subtherapeutic Posaconazole Exposure and Treatment Outcome in Patients With Invasive Fungal Disease.

BACKGROUND: Posaconazole exposure seems to be subtherapeutic in some patients with invasive fungal disease. Due to the pharmacokinetic variability of posaconazole, therapeutic drug monitoring may help to optimize the efficacy of this antifungal drug. METHODS: A retrospective study of patients treated with posaconazole from January 2008 to April 2014 and for whom posaconazole serum concentrations were available was conducted. Risk factors for underexposure of posaconazole were detected, and the relationship between posaconazole exposure and treatment outcome according to the European Organization for Research and Treatment of Cancer (EORTC) criteria was assessed. RESULTS: Seventy patients met the inclusion criteria, 45 patients received posaconazole as treatment, and 25 patients received posaconazole as a prophylactic. Posaconazole serum trough concentrations were <1.25 mg/L in 44.4% of patients receiving treatment and <0.7 mg/L in 40.0% of patients receiving prophylactic posaconazole. Multiple linear regression analysis showed a significant, independent, and negative association of the posaconazole serum trough concentration with a lack of enteral nutrition (P < 0.001), vomiting (P = 0.035), the use of a proton pump inhibitor or H2-receptor antagonist (P < 0.001), a liquid diet (P = 0.002), concomitant chemotherapy (P = 0.004), and a posaconazole dose frequency of 2 times daily (P = 0.015). A higher posaconazole concentration was associated with a better treatment outcome [odds ratio = 22.22 (95% confidence interval, 3.40-145.33); P = 0.001]. CONCLUSIONS: Posaconazole exposure is insufficient in more than 40% of patients at risk of or with invasive fungal disease, and posaconazole exposure is positively correlated with a successful treatment outcome. Therapeutic drug monitoring of posaconazole can detect underexposure and can be helpful in treatment optimization.

[PHARMACOGENOMICS AND PERSONALIZED MEDICINE: TOWARDS A SYSTEMATIC GENOMIC SCREENING?]. / PHARMACOGÉNOMIQUE ET MÉDECINE PERSONNALISÉE : VERS UN SCREENING SYSTÉMATIQUE DE LA POPULATION ?

Recent advances in medical genomics open new perspectives for personalized medicine through the identification of genetic variants that influence drug response and/or the risk of side effects. Today, the clinical applications of pharmacogenetics remain scarce as a consequence of the cost and turn-around-time of genetic tests. However, a few tests are recommended, for instance before the prescription of some anti-cancer agents or the anti-retroviral agent abacavir. In the future, we will probably move either towards rapid targeted tests or towards a large screening, before any diagnosis, of all the genetic factors influencing the therapeutic response. In that case, physicians will have to consult the patient genomic data before drug prescription in order to personalize the choice of the therapeutic agent or its dosage. However, such a genomic approach brings economical and ethical questions and will require further progress in our capacity to interpret and store the personal genomic data without compromising their confidentiality.

[BREAST CANCER: FROM TARGETED THERAPY TO PRECISION MEDICINE]. / CANCER DU SEIN : DE LA THÉRAPIE CIBLÉE À LA MÉDECINE PERSONNALISÉE.

The authors review the principles of systemic therapy in breast cancer. They analyze the degree of treatment individualization in our current approach. New technologies allow the detection of genomic alterations in cancer cells. Unfortunately, we do not know yet how to best use this knowledge for routine patient care. Most genomic alterations are rare events complicating further drug development. Temporal and spatial heterogeneity in tumors also has to be taken into account. An intense international collaboration is ongoing to try and demonstrate that precision medicine will really improve treatment outcome.

Inflammation is associated with voriconazole trough concentrations.

Voriconazole concentrations display a large variability, which cannot completely be explained by known factors. Inflammation may be a contributing factor, as inflammatory stimuli can change the activities and expression levels of cytochrome P450 isoenzymes. We explored the correlation between inflammation, reflected by C-reactive protein (CRP) concentrations, and voriconazole trough concentrations. A retrospective chart review of patients with at least one steady-state voriconazole trough concentration and a CRP concentration measured on the same day was performed. A total of 128 patients were included. A significantly (P < 0.001) higher voriconazole trough concentration was observed in patients with severe inflammation (6.2 mg/liter; interquartile range [IQR], 3.4 to 8.7 mg/liter; n = 20) than in patients with moderate inflammation (3.4 mg/liter; IQR, 1.6 to 5.4 mg/liter; n = 60) and in patients with no to mild inflammation (1.6 mg/liter; IQR, 0.8 to 3.0 mg/liter; n = 48). The patients in all three groups received similar voriconazole doses based on mg/kg body weight (P = 0.368). Linear regression analyses, both unadjusted and adjusted for covariates of gender, age, dose, route of administration, liver enzymes, and interacting coadministered medications, showed a significant association between voriconazole and CRP concentration (P < 0.001). For every 1-mg/liter increase in the CRP concentration, the voriconazole trough concentration increased by 0.015 mg/liter (unadjusted 95% confidence interval [CI], 0.011 to 0.020 mg/liter; adjusted 95% CI, 0.011 to 0.019 mg/liter). Inflammation, reflected by the C-reactive protein concentration, is associated with voriconazole trough concentrations. Further research is necessary to assess if taking the inflammatory status of a patient into account is helpful in therapeutic drug monitoring of voriconazole to maintain concentrations in the therapeutic window, thereby possibly preventing suboptimal treatment or adverse events.

Dust-climate couplings over the past 800,000 years from the EPICA Dome C ice core.

Dust can affect the radiative balance of the atmosphere by absorbing or reflecting incoming solar radiation; it can also be a source of micronutrients, such as iron, to the ocean. It has been suggested that production, transport and deposition of dust is influenced by climatic changes on glacial-interglacial timescales. Here we present a high-resolution record of aeolian dust from the EPICA Dome C ice core in East Antarctica, which provides an undisturbed climate sequence over the past eight climatic cycles. We find that there is a significant correlation between dust flux and temperature records during glacial periods that is absent during interglacial periods. Our data suggest that dust flux is increasingly correlated with Antarctic temperature as the climate becomes colder. We interpret this as progressive coupling of the climates of Antarctic and lower latitudes. Limited changes in glacial-interglacial atmospheric transport time suggest that the sources and lifetime of dust are the main factors controlling the high glacial dust input. We propose that the observed approximately 25-fold increase in glacial dust flux over all eight glacial periods can be attributed to a strengthening of South American dust sources, together with a longer lifetime for atmospheric dust particles in the upper troposphere resulting from a reduced hydrological cycle during the ice ages.

Investigating the potential of pyrazine dioxide based-compounds as organic electrodes for batteries.

Understanding structure-property relationship in redox-active molecular species is of central importance in various fields, including many medicinal and chemical applications. The quest for performant organic electrodes in the context of energy storage calls for pioneering studies to develop new and possibly optimal materials. Beyond modifying the molecular design of the existing compounds through functionalization, expansion of the search enabling the advent of efficient new backbones can potentially lead to breakthroughs in this research area. The number of already identified families able to constitute negative organic electrodes is much lower than that of their positive counterparts, which calls for finding ways to bridge this gap. To expand the dataset of known predicted redox potentials and in view of reaching an educated guess about the abilities of some eventual new redox active electrodes, we examined the properties of pyrazine N,N'-dioxide (PZDO) and its fully methylated functionalized derivative (TeMePzDO). The aspects and mechanisms driving the various features characteristic of these compounds were unraveled through molecular and periodic DFT calculations combined with accurate electronic structure analysis. The predicted molecular redox/crystalline intercalation potentials lead to the classification of PZDO and TeMePzDO systems within the class of negative electrodes, with features that are significantly appealing compared to those of some existing systems with backbones suited for such kind of application.

Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole.

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.